Novel homozygous variants in the SERPING1 gene in two Turkish families with hereditary angioedema of recessive inheritance.,Immunology and Cell Biology

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Novel homozygous variants in the SERPING1 gene in two Turkish families with hereditary angioedema of recessive inheritance.
Immunology and Cell Biology ( IF 3.2 ) Pub Date : 2020-05-23 , DOI: 10.1111/imcb.12362
Nihal Mete Gökmen ₁ , César Rodríguez-Alcalde ₂ , Okan Gülbahar ₁ , Margarita Lopez-Trascasa ₃ , Hüseyin Onay ₄ , Alberto López-Lera _{2,

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Affiliation

Hereditary angioedema as a result of deficiency of the C1 inhibitor (HAE‐C1INH; MIM# 106100) is a rare autosomal disorder and affected individuals are generally heterozygous for dominant negative variants in the SERPING1 gene. Homozygosity for SERPING1 pathogenic variants was long considered to be embryonically lethal; however, five nonrelated families with a recessive HAE pattern have been described in the last decade. In this report, we functionally characterized two newly reported nonrelated, consanguineous families with a recessive presentation of HAE attributed to SERPING1 variants in the reactive center loop (family D; S438F) and gate (family A; I379T) regions. S438F heterozygotes (family D) showed variable levels of intact 105‐kDa and cleaved/inactive 96‐kDa isoforms of C1INH, whereas their homozygous relative presented only the 96‐kDa band. Functional studies showed that S438F reduced C1INH interaction with target proteases in heterozygous (C1s, 32–38% of controls and FXIIa, 28–35% of controls) and homozygous (C1s, 18–24% of controls and FXIIa, 4–8% of controls) carriers, which is consistent with the more severe presentation of HAE in the family and decreased C1q levels in homozygous patients. By contrast, plasma C1INH from I379T heterozygotes (family A) showed normal C1INH/C1s binding (84–94% of controls) and no significant reduction in C1INH/FXIIa complexes (50–70% of controls). However, the homozygote failed to inhibit both C1s (25–42% of controls) and FXIIa (14–18% of controls). This profile is concordant with the less severe presentation of HAE in the family and the conserved C4 and C1q levels in heterozygous and homozygous patients.

中文翻译：

两个具有隐性遗传性遗传性血管性水肿的土耳其家族中 SERPING1 基因的新型纯合变异体。

由于 C1 抑制剂 (HAE-C1INH; MIM# 106100) 缺乏导致的遗传性血管性水肿是一种罕见的常染色体疾病，受影响的个体通常是SERPING1基因显性失活变异的杂合子。SERPING1致病变异的纯合性长期以来被认为是胚胎致死的；然而，在过去十年中已经描述了五个具有隐性 HAE 模式的不相关家族。在本报告中，我们对两个新报告的非血缘近亲家族进行了功能表征，这些家族具有归因于SERPING1的 HAE 隐性表现反应中心环（D 族；S438F）和门（A 族；I379T）区域的变异。S438F 杂合子（D 族）显示出不同水平的 C1INH 的完整 105-kDa 和切割/失活的 96-kDa 同种型，而它们的纯合子亲属仅呈现 96-kDa 条带。功能研究表明，S438F 降低了杂合子（C1s，32-38% 的对照和 FXIIa，28-35% 的对照）和纯合子（C1s，18-24% 的对照和 FXIIa，4-8%）中 C1INH 与靶蛋白酶的相互作用对照）携带者，这与家族中更严重的 HAE 表现和纯合子患者的 C1q 水平降低一致。相比之下，来自 I379T 杂合子（A 族）的血浆 C1INH 显示出正常的 C1INH/C1s 结合（84-94% 的对照），而 C1INH/FXIIa 复合物（50-70% 的对照）没有显着减少。然而，纯合子未能抑制 C1s（25-42% 的对照）和 FXIIa（14-18% 的对照）。该特征与家族中不太严重的 HAE 表现以及杂合子和纯合子患者中保守的 C4 和 C1q 水平一致。

更新日期：2020-05-23

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